N-directed aliphatic C-H borylation using borenium cation equivalents

Article abstract of DOI:10.1021/ja208093c

Highly electrophilic boron cations derived from hindered amine borane complexes have been shown to undergo intramolecular aliphatic C-H borylation.

Full text of DOI:10.1021/ja208093c

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N-Directed Aliphatic CÀH Borylation Using Borenium
Cation Equivalents
Aleksandrs Prokofjevs and Edwin Vedejs*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S Supporting Information
b
Scheme 1
ABSTRACT: Highly electrophilic boron cations derived
from hindered amine borane complexes have been shown to
undergo intramolecular aliphatic CÀH borylation.
ricoordinate boron inserts into CÀH bonds upon heating.1À5
T
In the first report, Hurd studied the reaction of B2H6 with
several substrates, including benzene (100 °C) and methane
(180 °C), and found evidence for the formation of phenylboron
compounds and, indirectly, methylboron species, respectively.1
Related intramolecular CÀH insertion reactions were subse-
quently identified2,3 and were explored in depth by K€oster et al.3
However, typically extreme conditions (ca. 200À300 °C), vari-
able regioselectivity, and substrate limitations may have discour-
aged further development. According to computational evaluation,
the borylation of aliphatic CÀH bonds involves a four-center
mechanism.5,6 Some of the relatively facile electrophilic
borylations of aromatic substrates by tethered tricoordinate
boron species may also follow a CÀH insertion pathway,4 but
an electrophilic aromatic substitution mechanism is a plausi-
ble alternative in most cases, pending definitive evidence.
Related CÀH insertions may also take place in the gas-phase
reactions of simple alkanes with cationic, dicoordinate boron
intermediates (borinium cations) under flowing afterglow
conditions.7
Scheme 2
Stimulated by intensive recent interest in transition-metal-
mediated borylations using CÀH insertion chemistry,8À10 we have
explored the possibility that nitrogen-tethered cationic tricoordi-
nate boron species (borenium salts) may have similar reactivity. As
described below, several examples of borenium CÀH insertion
have now been demonstrated under more promising conditions
compared to the thermal methods reported for neutral boranes.
Treating the hindered amine borane complex 1 with a 50 mol %
loading of the strong electrophile Tr[B(C6F5)4] predictably
resulted in formation of the H-bridged cationic boron inter-
mediate 2, with δ(11B) = À1.1 ppm in C6D5Br (Scheme 1).11
Further addition of the electrophilic trityl salt induced rapid
formation of a tricoordinate boron species, as evidenced by
a broad signal at +69.3 ppm in the 11B NMR spectrum within
10 min at room temperature.12 Over the same time scale, the
1H NMR spectrum showed the disappearance of the t-Bu singlet
of 2 [δ(1H) = 0.86 ppm] and the appearance of two new singlets
[δ(1H) = 0.64 and 1.27 ppm; 6:2 integral ratio]. Together with
the substantial downfield shift of the broad BÀH resonance
[δ(1H) = 4.8 ppm] and liberation of H2, these and other
spectroscopic data [see the Supporting Information (SI)] are
consistent with the spirocyclic borenium structure 4. At no time
was the open-chain borenium cation 3 detected. Interestingly, 4
constitutes a rare example of a tricoordinate boron cation lacking
stabilizing n- or π-donor groups.13 Additionally, 4 is a represen-
tative of the uncommon BÀH borenium ion class; only a few
such compounds have been reported to date.4,14 A hydride
quench with n-Bu4NBH4 converted 4 to the isolable amine
borane 5 (82% yield), which was readily identified by the broad
CH2B 1H and 13C NMR signals (0.75 and 31 ppm, respectively,
in CDCl3) and an H-coupled triplet at À4.2 ppm in the 11B NMR
spectrum.
In search of further improvement of the protocol, Tf2NH was
evaluated as the “hydridophile” (Scheme 2). The composition
of activated intermediates was greatly influenced by the solvent
and the 1/Tf2NH ratio. Thus, the stoichiometric reaction in
toluene-d8 afforded the covalent adduct 6.15 The same adduct 6
was also seen in toluene-d8 using 5 mol % Tf2NH for activation,
Received: August 26, 2011
Published: November 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja208093c J. Am. Chem. Soc. 2011, 133, 20056–20059
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Scheme 3. Catalytic CÀH Borylation Using Tf2NH
Table 1. Catalytic CÀH Borylation Using Tf2NH Activationa
Activation
products (isomer ratio;
entry
substrate
solvent
% isol)
1
2
1
8
C6H5F
C6H6
5 (75%)
9 (96%)
3
10b
10e
10e
12
15
18
22g
C6H5F
C6H5F
C6H5F
toluene
toluene
toluene
toluene
11 (14%), 10 (63%)c
11 (13%), 10 (45%)
11 (25%), 10 (35%)
13, 14 (12:1; 78%)
16, 17 (20:1; 95%)
19, 20, 21 (25:7:1; 89%)
23, 24 (25:1; 96%)
4d
5f
6
7
8
9
a Conditions: 5 mol % Tf2NH, sealed tube, 160 °C, 14 h unless otherwise
noted, quenched with n-Bu4NBH4. b 1:1 dr or single diastereomer. c 20%
conversion, NMR assay. d 10 mol % Tf2NH, 60 h. e Single diastereomer.
f 10 mol % Tf2NH, 60 h, pressure vented four times during thermolysis.
g 24 h.
amine boranes, furnishing organoboron structures that are not
available via the conventional hydroboration route. Thus, amine
boranes 1 and 8 cleanly formed products 5 and 9, respectively
(Table 1, entries 1 and 2). In contrast, the usual procedure with
substrate 10 gave only 20% conversion (entry 3; a 14% yield of 11
isolated), from either a single diastereomer or a 1:1 mixture.
Increased catalyst loading (10%) and prolonged heating (60 h)
did not improve the conversion (entry 4). The yield of 11 was
higher (25%) when the hydrogen pressure was periodically
vented (entry 5 vs entry 4), but the reaction stalled as before.
Cyclization of the aliphatic amine borane 12 afforded spiro-
cycle 13 as the major product (entry 6), revealing the preferred
CÀH insertion reactivity as methyl > methylene. Because of
difficulties in isomer separation, the minor product 14 was
characterized as an enriched mixture.
To address the regioselectivity further, substrate 15 was tested
under the catalytic conditions (entry 7). The aromatic borylation
product 16 predominated, although the aliphatic borylation
product 17 was also detected.16,17 The cyclization of the related
substrate 18 was more complex (entry 8), although the major
product 19 reflects a similar preference for borylation at the
methyl CÀH over the methylene CÀH, as seen with 12 (entry 6).
The minor product 21 also contains a new aliphatic CÀB bond,
while the unusual tricyclic product 20 contains aryl as well as
aliphatic CÀB bonds, apparently as a result of a second boryla-
tion event with loss of H2. As evidenced by in situ NMR
spectroscopy between 120 and 160 °C, the formation of 20
began only after most of the 18 had been converted to 19,
suggesting that the aromatic borylation event leading to 20 is the
slower cyclization step in this sequence. In the absence of a
suitably placed aliphatic CÀH bond, the same reaction condi-
tions induced efficient aromatic borylation from 22 to a 25:1
mixture of 23 and 24 (entry 9). It is interesting that a related
stoichiometric borylation4 afforded a markedly different 23:24
ratio of 1:1.3, indicating a change in the product-determining
steps.18
but the H-bridged cation 7 was also detected as the activated
species in CD2Cl2. Subsequent events were also influenced by
the 1/Tf2NH ratio. With 5 mol % Tf2NH in toluene, clean
catalytic cyclization to 5 and H2 was observed above 120 °C. In
contrast, heating the covalent adduct 6 under the same condi-
tions mostly afforded decomposition products.
The high stability of the bistriflimide anion paired with the
good solubility of its derivatives in aromatic solvents allowed the
development of a simple catalytic procedure that could be used
with a range of substrates (Scheme 3 and Table 1). The same 5%
loading of the catalyst Tf2NH was used in most cases, and the
reactions were performed in sealed vials at 160 °C without
attempting to define the threshold temperature for each example.
After the reaction was quenched with n-Bu4NBH4 to convert
borenium equivalents derived from the 5% Tf2NH to amine
boranes, simple filtration through silica gel to retain polar
bistriflimide-containing byproducts gave clean isomer mixtures
in most cases. The products were further purified by crystal-
lization or chromatography, and structures were assigned by
multinuclear NMR spectroscopy and high-resolution mass spec-
trometry (HRMS) (see the SI).
While the formation of 4 from 2 under the influence of added
electrophile (Scheme 1) parallels observations in the previously
reported aromatic borylation,4 the events after the formation of
7 in the catalytic reaction remain unclear. The substantial rate
difference between the stoichiometric and catalytic processes
raised suspicions that perhaps the rate of the catalytic process
The intramolecular borylation method is particularly efficient
for forming CÀB bonds next to quaternary centers in hindered
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COMMUNICATION
Scheme 4
Figure 1. ORTEP plot of 25 (the counterion has been omitted for
clarity). The part of the structure to the left of H1 is disordered. Selected
bond lengths (Å) and angles (deg): B1ÀN1, 1.58; N1ÀC1, 1.48;
N1ÀC2, 1.48; N1ÀC3, 1.48; B1ÀN1ÀC1, 112; B1ÀN1ÀC2, 106;
B1ÀN1ÀC3, 112.
examples in Scheme 3, insertion into methyl CÀH bond is
strongly favored over insertion into the methylene CÀH
bond. Further experimental and computational investigations
of this unusual transformation are ongoing and will be reported
separately.
may be limited by slow regeneration of the H-bridged inter-
mediate 2 (Scheme 2), corresponding to the reaction of bor-
enium salt 4 with amine borane 1 in the stoichiometric reaction.
However, when a solution of 4 in C6D5Br was treated with 2
’ ASSOCIATED CONTENT
equiv of Me3N BH3 at room temperature, the symmetrical
3
H-bridged cation 2511 was detected by NMR assay among other
S
Supporting Information. Experimental procedures, X-ray
b
products. This observation provides evidence of facile intermo-
crystallography data (CIF), NMR spectra and computational
results. This material is available free of charge via the Internet at
http://pubs.acs.org.
lecular hydride transfer from Me3N BH3 to 4, and by analogy
3
from 1 to 4, and suggests that other steps in the catalytic process
control the rate of catalyst turnover (see the discussion of
Scheme 4 below).
’ AUTHOR INFORMATION
To confirm the assignment, 25 was prepared independently by
treating Me3N BH3 with 0.5 equiv of Tr[B(C6F5)4] in dry
3
Corresponding Author
edved@umich.edu
benzene (eq 1), and the structure was established by X-ray
crystallography (Figure 1).19 Prior studies have proposed related
structures based on NMR evidence or theoretical considera-
tions.11,20,21
’ ACKNOWLEDGMENT
This work was supported by the National Institute of General
Medical Sciences of the NIH (GM067146). The authors thank
Dr. J. W. Kampf for the X-ray structure determination of 25.
In response to review, hypothetical catalytic cycles are drawn
in Scheme 4. The activation and quenching steps are well-
defined, and regeneration of the activated precatalyst ii via
hydride transfer from the starting amine borane i to the initial
product v is plausible. However, it would be too early to propose
a rate-determining step. The borocations mentioned within the
black box include borenium salts or their hydride-bridged
equivalents, but several other cations are conceivable in view of
the rich chemistry of amine boranes. The high temperature
required for the catalytic method suggests that activated species
other than 7 are present,22 in contrast to the stoichiometric
reaction, but a role for 7 is not excluded.
In summary, we have shown the feasibility of N-directed CÀH
borylation via borocations derived from hindered amine BH3
complexes using either stoichiometric or catalytic activation by
strong electrophiles. When performed using stoichiometric
Tr[B(C6F5)4], cyclization of 1 proceeds at ambient temperature,
generating the unique unstabilized BÀH borenium salt 4 and
hydrogen. This observation demonstrates that the inherent
barrier for CÀH insertion is quite low. Although the correspond-
ing catalytic process using Tf2NH activation requires temperatures
above 120 °C for catalyst turnover on a practical time scale, the
borylation products are formed cleanly. According to several
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(15) Compound 6 exists as a mixture of O- and N-bound NTf2
isomers according to multinuclear NMR data. The 13C and 19F signals
are decisive (13C: three F-coupled quartets at 120.5, 120.2, and 119.6
ppm; 19F: three signals in a 0.74:1:1 ratio at À69.2, À76.7, and À78.8
ppm; 11B: two signals at 0.6 and À4.6 ppm), and the presence of a
stereogenic S atom in one of the isomers is evident from the 1H and 13
NMR spectra. See the SI for additional details.
C
(16) A related aromatic borylation using catalytic Tr[B(C6F5)4] was
briefly mentioned in ref 4, but Tf2NH gives a cleaner reaction.
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2011, 50, 2102. Also see refs 4 and 13.
(18) The following data exclude differences in solvent and activating
agent vs ref 4: (a) 22 + 0.9 equiv of Tr[B(C6F5)4]/PhF, 4 h (rt):
23:24 = 1.1:1. (b) 22 + 5 mol % Tr[B(C6F5)4]/PhF, 24 h (160 °C):
23:24 = 17:1.
(19) Additional X-ray crystallography data and computational anal-
ysis of 25 are available in the SI.
(20) Stephens, F. H.; Baker, R. T.; Matus, M. H.; Grant, D. J.; Dixon,
D. A. Angew. Chem., Int. Ed. 2007, 46, 746.
(21) During review of this manuscript, the X-ray structure of a more
highly stabilized analogue of 25 was reported. See: Inꢀes, B.; Patil, M.;
Carreras, J.; Goddard, R.; Thiel, W.; Alcarazo, M. Angew. Chem., Int. Ed.
2011, 50, 8400.
(22) In the simplest example, 25 generated in situ using 30 mol%
Tr[B(C6F5)4] in C6D5Br decomposed at >120 °C. After 19 h at 160 °C, a
11B NMR assay showed new proton-coupled signals at 3.2 and À2.4 ppm and
complex signals between À14 and À19 ppm. If analogous hydride-bridged
cations are required intermediates in the catalytic borylations, then their
decomposition may explain the low conversion from 10 to 11.
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